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Experiments were designed to determine if the inotropic response to increasing buffer calcium concentration differs in male and female cardiac muscle. Left atrial and papillary muscles were isolated from hearts of 3-4-month old male and female rats, bathed in Krebs-Henseleit solution (30 degrees C), and stimulated at 1.5 Hz. Isometric developed tension was monitored continuously as extracellular Ca2+ was increased in a cumulative fashion. When compared to male atrial muscle, female atrial preparations were more sensitive to the resulting positive inotropic action; EC50 values were 2.89 +/- 0.22 and 1.86 +/- 0.21 mM in male and female atria, respectively. Two-way analysis of variance (ANOVA) also indicated that there was a significant gender-associated difference in the Ca2+ dose-response curves in atrial muscle. In contrast, papillary muscle did not show a significant gender-related difference in EC50 values (0.88 +/- 0.07 and 0.74 +/- 0.06 mM in males and females); however, the Ca2+ dose-response curves obtained from male and female preparations were found to be significantly different when compared by ANOVA.

The antiarrhythmic agent lidocaine reduces inward sodium current and increases outward potassium current. Described studies investigated the effect of lidocaine on circulating and urinary levels of atrial natriuretic peptides in an intact canine model. Surface electrocardiography was monitored along with right ventricular, left ventricular and aortic pressures, and cardiac output. Plasma and urine atrial natriuretic peptides were measured immediately before and five minutes after a five minute, 2 mg/min, intravenous lidocaine infusion. Long acting natriuretic peptide (LANP), vessel dilator, and atrial natriuretic factor (ANF) were monitored by RIA. There were no measured hemodynamic or cardiomechanical changes noted after lidocaine infusion. Similarly, there was no change in plasma sodium or potassium, or urine sodium. There was, however, an increase in urine potassium levels. Additionally, plasma and urine LANP and ANF peptide levels were increased following lidocaine infusion, while plasma and urine concentrations of vessel dilator were not changed. These data suggest that lidocaine increases plasma and urine atrial natriuretic peptides by mechanisms other than cardiodepression and/or vasodilation.

Studies were designed to determine if tetramethylammonium (TMA), a quaternary amine that structurally resembles the cationic portion of acetylcholine, can affect cardiac function by acting on muscarinic receptors. Experiments examined effects of this cation on 1) the spontaneous beating rate of right atrial preparations isolated from rats, 2) force of contraction in isoproterenol-treated (0.1 microM) rat papillary muscle, and 3) quinuclidinyl benzilate ([3H]QNB) binding to rat ventricular membranes. TMA elicited concentration-dependent (0.5-50 mM) negative chronotropic and negative inotropic actions that were antagonized by the muscarinic receptor antagonist atropine. Radioligand studies showed that TMA acts as both a competitive and noncompetitive antagonist of [3H]QNB binding; the apparent dissociation constant for [3H]QNB was increased (0.092 +/- 0.025 nM in the absence of TMA; 1.14 +/- 0.204 nM in the presence of 50 mM TMA), whereas binding site density was decreased (148 +/- 26 and 65 +/- 4 fmol/mg in the absence and presence of 50 mM TMA, respectively). These results suggest that extracellular TMA can alter the function of rat heart by stimulating muscarinic receptors. This action should be considered when using this quaternary amine as a cation substitute.

Luteolin, a flavone present in many foods and medicinal plants, may have beneficial effects on various human chronic diseases. In the present study, we investigated the hypothesis that luteolin can directly act on vascular endothelial cells (ECs), leading to nitric oxide (NO) production and subsequent vascular relaxation. Rat aortic rings were mounted in organ bath. Luteolin was added cumulatively, and vessel relaxation of rat aortic rings precontracted with phenylephrine (PE) or potassium was recorded. Endothelial nitric oxide synthase (eNOS) phosphorylation at Ser1177 and NO production from aortic rings and primary human aortic endothelial cells (HAECs) exposed to luteolin were measured by using Western blot and fluorometric assay, respectively. Luteolin dose-dependently (10–100 μmol/L) elicited relaxation of PE- or potassium-contracted aortic rings. The vasorelaxation effect of luteolin was attenuated by the eNOS inhibitor, N-nitro-l-arginine methyl ester, suggesting that this luteolin action is at least partially mediated by activating eNOS activity. We further found that luteolin dose-dependently (10–100 μmol/L) increased eNOS phosphorylation at Ser1177 (up to 1.9-fold) in isolated rat rings. Consistently, exposure of HAECs to luteolin also increased eNOS phosphorylation and NO production. Luteolin may be a vascular protective agent by directly acting on vascular ECs to stimulate NO-dependent vascular dilatation.

This study correlated plasma lipid values with angiographic evidence of progression to complete coronary occlusion. Baseline triglycerides (TGs), total cholesterol (Chol), high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, very low density lipoprotein (VLDL) cholesterol, and HDL/LDL and HDL/Choi ratios were compared with coronary angiograms taken at baseline, 3 and 5 years in a prospective angiographic study. Results were from part of the multicenter trial of plasma lipid reduction in patients after a single myocardial infarction (POSCH). Comparison of patient’s baseline lipids in the absence or presence of a new total coronary occlusion at 3 years showed a significant difference (p = 0.01) in TGs of 197 ± 147 versus 250 ± 162 mg/dl (p = 0.02) and VLDL of 30 ± 23 (n = 284) versus 40 ± 30 (n = 49) mg/dl. Stratification by the mean HDL/Chol ratio (16%) demonstrated that baseline TG levels were significantly increased in patients with a new coronary occlusion by 3 years despite a higher HDL/Choi ratio. When measured at the 3-year visit, plasma TG (176 ± 91 versus 212 ± 146 mg/dl; p = 0.02) and VLDL (28 ± 18 versus 35 ± 29 mg/dl; p = 0.04) were significantly elevated in the presence of a new 3-year coronary occlusion. Stratification by the mean HDL/Choi ratio (16%) demonstrated that 3-year TG levels increased significantly in patients with a new 3-year coronary occlusion despite a higher HDL/Chol ratio. A comparison of the baseline lipid results with angiographic evidence of occlusion by 5 years showed a significant difference (p = 0.04) in Chol in patients with a new total coronary occlusion (255 ± 35 mg/dl) versus patients without a new total coronary occlusion (247 ± 30 mg/dl). Both LDL and the HDL/LDL ratio were not significantly different between groups. When measured at 5 years, TGs were higher in patients who did (213 ± 165 mg/dl) than in patients who did not (182 ± 91 mg/dl) occlude by 5 years (p

Release rate constants and disappearance rate constants were determined for three atrial natriuretic peptides consisting of amino acids 1–98 (i.e., proANF 1–98), the midportion of the ANF prohormone consisting of amino acids 31–67 (i.e., proANF 31–67) and amino acids 99–126 (i.e., ANF) after right ventricular pacing at 100, 125, 150, and 180 bpm in six male mongrel dogs. Right atrial and femoral vein blood was obtained at baseline, and at 5, 12, 19, 26, 56, 86, 116, 146, and 206 minutes after right ventricular pacing. Resulting plasma concentration-time data derived parameters were compared. The disappearance rate constants for atrial and femoral venous proANF 1–98 were 0.0144 ± 0.0087 (X ± SD) and 0.0175 ± 0.0075 min−1, respectively (t = 0.6158) and release rate constants were 0.1569 ± 0.1504 and 0.0670 ± 0.0393 min−1, respectively (t = 1.8269; P > .05). The proANF 31–67 disappearance rate constants were 0.0139 ± 0.0082 and 0.0148 ± 0.0132 min−1, respectively (t = 0.1192) and release rate constants were 0.0957 ± 0.0414 and 0.1984 ± 0.1762 min−1, respectively (t = 1.4812). The ANF elimination phase disappearance rate constants were 0.0663 ± 0.0273 and 0.1116 ± 0.0539 min−1 (t = 2.0923, P > .05), respectively, and the release rate constants were 0.1335 ± 0.0532 and 0.1638 ± 0.0520 min−1 (t = 0.7878, P > .05), respectively. These data indicate that proANF 1–98 and proANF 31–67 circulating β post-distribution half-lives are approximately 45 minutes whereas β half-life of ANF is 10 minutes. Persisting concentrations of proANF 1–98 and proANF 31–67 in plasma may better explain the proported sustained pharmacologic effects that have been attributed to ANF, which has a mean a distribution phase half-life of 3.5 minutes and a β half-life of 10 minutes.

Recently two peptides consisting of amino acids (aa) 1 to 30 and 31 to 67 of the N-terminus of the 126 aa prohormone of atrial natriuretic factor (proANF), as well as atrial natriuretic factor (ANF, aa 99 to 126; C-terminus), were found to have vasodilatory and natriuretic properties. These peptides, as well as ANF, circulate in humans as part of the N-terminus of the prohormone. To determine the effect of graded exercise on the circulating concentrations of the N-terminus and C-terminus of the ANF prohormone in normal persons, 12 healthy individuals (mean age 45 +/- 2 years) were evaluated before, for 2 hours after, and during bicycle exercise at a work loads of 25, 50, 75, 100, 125, 150, and 175 W. Both the N- and C-terminus of the ANF prohormone were released simultaneously with graded exercise in direct proportion to the intensity of the work load, measured objectively via maximal oxygen consumption (VO2max), respiratory quotient, and heart rate. Both the N-terminus and C-terminus of the ANF prohormone had strong positive correlations (p less than 0.001) with blood pressure, heart rate, VO2max, and respiratory quotient. Following exercise, the C-terminus returned to preexercise levels within 30 minutes, while the N-terminus remained significantly elevated at 30 and 60 minutes postexercise, reflecting the longer half-life of the N-terminus in the circulation.

Female subjects have been reported to be less sensitive to the hyperthermic effects of 3,4-methylenedioxymethamine (MDMA) than males. Studies were designed to examine the cellular mechanisms involved in these sex sensitive differences. Gonadectomized female and male rats were treated with a 200 {mu}g 100 {mu}L{sup -1} of estrogen or 100 {mu}g 100 {mu}L{sup -1} of testosterone respectively every 5 days for a total of three doses. Rats were then challenged with either saline or MDMA (20 mg kg{sup -1}, sc). Rats were then euthanized and aortas were constricted, in vitro, by serial phenylephrine (Phe) addition with or without the inhibitor of nitric oxide (NO) synthase, g-nitro-L-Arginine-Methyl Ester (L-NAME). Skeletal muscle uncoupling protein-3 (UCP3) expression was measured as well as plasma norepinephrine (NE) levels. All males but no females developed hyperthermia following MDMA treatment. The EC{sub 50} for Phe dose response curves increased only in the females treated with MDMA and T{sub max} for Phe increased following L-NAME only in the females. Both males and females demonstrated an increase in plasma NE following MDMA treatment; however, males displayed a significantly greater NE concentration. Skeletal muscle UCP3 expression was 80% less in females than in males. These results suggest that the inabilitymore » of MDMA to induce a thermogenic response in the female subjects may be due to four sex-specific mechanisms: 1) Female subjects have reduced sympathetic activation following MDMA challenge; 2) Female vasculature is less sensitive to {alpha}{sub 1}-AR stimulation following MDMA challenge; 3) Female vasculature has an increased sensitivity to NO; 4) UCP3 expression in skeletal muscle is less in females.« less

Summary The N-terminus consisting of amino acids (a.a.) 1–98 (i.e., proANF 1–98), C-terminus (i.e., ANF; a.a. 99–126) and midportion of N-terminus consisting of a.a. 31–67 (proANF 31–67; Vessel Dilator) of the 126 a.a. ANF prohormone were present in the urine in 5-to-8-fold increased concentrations versus their plasma concentrations in 6 dogs under basal conditions. With acute coronary occlusion the right atrial plasma concentrations of these peptides increased two-to-three-fold, while in the urine only proANF 31–67 increased (3.5-fold). Ventricular fibrillation caused a 4-to-10-fold increased secretion into the right atrial chamber with a simultaneous 3-to-4.7-fold increase in the urine of proANF 1–98, proANF 31–67, and ANF. This investigation demonstrates that proANF 1–98, proANF 31–67 and ANF are normally present in urine and increase in the urine with cardiac stimuli that cause their release from the heart.

The progression of coronary artery stenosis to total occlusion was assessed in 413 hyperlipidemic patients with a previous myocardial infarction. Coronary angiograms were recorded at baseline, 3 (n = 312), and 5 years (n = 248) after initial study and analyzed by 2 independent readers. There were 177 (43%) patients with 1-, 130 (31%) with 2-, and 61 (15%) with 3-vessel disease (greater than or equal to 50% diameter narrowing), whereas 45 (11%) did not have significant disease within a major coronary vessel at baseline. A new finding of total occlusion occurred in 4% (30 of 748) and 7% (40 of 605) of major coronary artery segments at 3 and 5 years, respectively. The risk of progression to total occlusion was higher if the initial stenosis was greater than 60% compared to lesions less than or equal to 60% both at 3 years (19 of 143 = 13% vs 11 of 605 = 2%; p less than 0.001) and 5 years (27 of 91 = 30% vs 13 of 514 = 3%; p less than 0.001). The frequency of occlusion was highest for the right coronary artery by 5 years (18 of 167 = 11% for right vs 8 of 225 = 4% for circumflex vs 14 of 213 = 7% for left anterior descending coronary arteries; p less than 0.02). Clinical and laboratory data revealed that myocardial infarction was associated with a new total occlusion in 23% of patients (7 of 30) at 3 years and in 64% (25 of 39) at 5 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Experiments were designed to determine if gender influences the cardiac toxicity elicited by chronic high-level ethanol intake. Male and female ethanol-preferring P-rats were allowed free access to drinking water or water containing 25% ethanol for 6 months. Left atrial preparations were then isolated, bathed in Krebs-Henseleit solution (37 degrees C), and used to examine basal contractility at 3.0 Hz stimulation, the force-frequency relationship, and the positive inotropic response to the beta-adrenoceptor agonist isoproterenol. Basal contractile function was not affected significantly by ethanol in either gender; however, atria from ethanol-treated male rats displayed diminished contractility compared to control males when measured at slow stimulation frequencies (0.1 and 0.2 Hz), during post rest potentiation (at rest intervals of 20-60 s), and in response to higher concentrations of isoproterenol (or =3 x 10(-7) M; EC50 values were not affected). In contrast, female atria showed no effect of chronic ethanol consumption. These data suggest that ethanol consumption diminishes the cardiac reserve in male, but not female rats.

The effect of aging on cardiac membrane currents remains unclear. This study examined the inward rectifier K+ current ( I K1), the transient outward K+current ( I to), and the L-type Ca2+ channel current ( I Ca,L) in ventricular myocytes isolated from young adult (6 mo) and aged (>27 mo) Fischer 344 rats using whole cell patch-clamp techniques. Along with an increase in the cell size and membrane capacitance, aged myocytes had the same magnitude of peak I K1 with a greater slope conductance but displayed smaller steady-state I K1. Aged myocytes also had a greater I to with an increased rate of activation, but the I to inactivation kinetics, steady-state inactivation, and responsiveness to l-phenylephrine, an α1-adrenergic agonist, were unaltered. The magnitude of peak I Ca,L in aged myocytes was decreased and accompanied by a slower inactivation, but the I Ca,L steady-state inactivation was unaltered. Action potential duration in aged myocytes was prolonged only at 90% of full repolarization (APD90) when compared with the action potential duration of young adult myocytes. Aged myocytes from Long-Evans rats showed similar changes in I toand I Ca,L but an increased I K1. These results demonstrate aging-associated changes in action potential, in morphology, and in I K1, I to, and I Ca,L of rat ventricular myocytes that possibly contribute to the decreased cardiac function of aged hearts.

Initial experiments were designed to determine if vasoactive concentrations of nitric oxide (NO) alter contractility in rat heart. Contractile function was monitored in left atrial and papillary muscles (30 degrees C; paced at 0.5 Hz) during cumulative addition of 3-morpholino-sydnonimine-HCl(SIN-1), an agent that releases NO. At concentrations between 10(-7) and 10(-4) M (NO concentrations of approximately 10(-8)- 3 x 10(-7) M), SIN-1 did not affect contractility in either tissue. Similarly, 10(-4) M SIN-1 did not alter the positive inotropic responses to isoproterenol or increasing extracellular [Ca+2] ([Ca+2]o). To obtain higher concentrations of NO, additional studies were conducted using authentic NO. NO-saturated stock solutions and a corresponding control solvent were adjusted to pH 1.6 with HCl. Dose-dependent effects of NO were examined by adding aliquots of the stock solutions (or control solvent) to the bathing solution. At final concentrations of 1 x 10(-5)- 5 x 10(-4) M, NO produced transient, concentration-dependent decreases in contractility that were paralleled by reductions in buffer pH. Control solvent elicited similar reductions in pHo and transient decreases in contractility; however, the negative inotropic action elicited by the NO-containing solution was approximately 20% greater than that observed in control conditions. These data demonstrate that only high concentrations of NO depress contractility in isolated rat cardiac muscle, and suggest that this effect is mediated by both acidosis and a pHo-independent mechanism.

To assess whether infarct size, ischemic area and/or survival correlates with circulating atrial natriuretic peptides (long acting sodium stimulator, vessel dilator, or atrial natriuretic factor), these peptides were measured in a canine model of acute myocardial infarction. Elevations in the circulating concentrations of atrial natriuretic factor, vessel dilator, and long acting sodium stimulator were significant (P0.05) within 6 min of coronary occlusion of the left anterior descending coronary artery. The percentage of ischemic myocardium ranged from 20 to 67% with a mean of 37 +/- 17%. The area of infarction ranged from 1 to 13% with the infarcted area of non-survivors being twice that of survivors. Both the ischemic and infarcted areas correlated (P0.05) with the circulating concentrations of these atrial natriuretic peptides. Survival correlated also with the circulating plasma concentrations of vessel dilator, atrial natriuretic factor and long acting sodium stimulator (P0.05). When these circulating concentrations were evaluated, however, by determining their area under their respective concentrations curves and expressing each as the log area under plasma concentration-time curve (area under the curve) per kg of weight (Y = 58.48X-23.62; r = 0.825; P = 0.0009), vessel dilator was the only atrial natriuretic peptide that correlated with survival.

To determine whether heart rate contributes to release of three new peptide hormones synthesized in the heart, right ventricular pacing at rates of 100, 125, 150, and 180 bpm was performed in six dogs with measurement of the plasma concentration of these peptides at each pacing rate while right atrial and systemic blood pressures were simultaneously monitored. These three peptides of the 126-amino-acid prohormone of atrial natriuretic factor (ANF), consisting of amino acids 1-30 (pro ANF 1-30), 31-67 (pro ANF 31-67), and 99-126 (ANF), increased incrementally at paced heart rates of 125, 150, and 180 bpm (r = 0.8, p less than 0.001). Right atrial pressure decreased with increasing heart rate but systemic blood pressure did not decrease until the heart rate was 180 bpm, at which time these peptides had obtained their maximal circulating concentrations. After pacing, mean right atrial pressure and levels of ANF returned to prepacing values within 30 minutes. Mean arterial blood pressure, on the other hand, increased throughout the 120-minute period after pacing. At 2 hours after pacing, levels of pro ANFs 1-30 and 31-67 were elevated compared with prepacing values. These data demonstrate that, at heart rates of 125 bpm and above, pro ANF 1-30, pro ANF 31-67, and ANF (99-126) are simultaneously and incrementally released in direct proportion to heart rate. The sustained elevation in pro ANFs 1-30 and 31-67 seen 2 hours after pacing suggests that they may contribute to the prolonged diuresis seen after cardiac pacing or tachycardia.

The present investigation was designed to determine if acute ischemic cardiac injury causes the release of atrial natriuretic factor (ANF). Seventeen patients with acute myocardial infarction but without clinical evidence of congestive heart failure had their circulating concentration of ANF and creatine phosphokinase monitored daily for 14 days. All 17 patients had an elevated plasma ANF concentration at time of presentation. Maximal increase in ANF was on day 2 and 3 post-infarction. This maximal increase correlated with the size of infarction estimated by the maximal creatine phosphokinase concentration (r = 0.475; p less than 0.05), but did not correlate with the amount of left ventricular dysfunction. ANF began to decrease by day 4 post-infarction and was normal at 10 days post-infarction in 14 of the 17 (82%) patients. At 12 days post-infarction, all 17 patients had normal ANF levels. Another three patients with acute myocardial infarction were treated with tissue plasminogen activator (tPA). The measured ANF levels in these patients were within our normal range and were significantly lower (p less than 0.001) than those seen in patients with acute myocardial infarction not given thrombolytic therapy. Six patients with unstable angina likewise had normal circulating ANF concentrations during prolonged episodes of chest pain. These levels were also significantly lower (p less than 0.001) than the 17 patients with acute infarcts not given tPA. The distinct pattern of release of ANF may be useful as an adjunct to serum cardiac enzymes in determining if a myocardial infarction has occurred.

Fourteen patients with acute myocardial infarction (duration of chest pain 5 +/- 2 hours) received intracoronary infusion of prostaglandin E1 (PGE1) and streptokinase. Intracoronary PGE1 was followed by intracoronary streptokinase in 10 patients (group A), with successful recanalization in all patients. Of 4 patients in whom recanalization failed with intracoronary streptokinase given first (group B), 2 had successful recanalization after addition of intracoronary PGE1. Immediately after successful recanalization, left ventricular ejection fraction increased from 50 +/- 9% to 62 +/- 10% (p less than 0.0008), left ventricular end-diastolic pressure decreased from 20 +/- 10 to 16 +/- 10 mm Hg (p less than 0.05) and stroke volume index increased from 34 +/- 10 to 44 +/- 12 ml/m2 (p less than 0.02). Infarct segment shortening improved from 9 +/- 5 to 18 +/- 4% (p less than 0.0002). Transient hypotension in 1 patient was the only complication. Follow-up catheterization in recanalized patients at 2 to 10 days showed maintained improvement in left ventricular global and infarct segment function. Reocclusion occurred in 1 patient. Thus, intracoronary infusion of PGE1 was effective in establishing reperfusion in all patients when followed by streptokinase and was associated with immediately improved left ventricular global and regional function. PGE1 deserves further evaluation in acute myocardial infarction.

Out-of-hospital ventricular fibrillation (OHVF) is the most common cause of sudden cardiac death. Of 1,070 patients with OHVF who entered this study, 150 were discharged alive. Of this group, 120 were free of anoxic brain damage. Of these survivors, 67 (57%) had no previously demonstrated anginal symptoms. Treadmill stress testing revealed painless ST depression in 76% of these neurologically intact patients. Exercise ventriculography in a subset of 9 patients without angina before OHVF and in 6 patients with typical anginal symptoms revealed marked left ventricular dysfunction with ST depression in the absence of chest pain in all 15 patients. Sublingual nitroglycerin reversed this evidence of ischemia in the asymptomatic patients. Patients were followed for 6 years after discharge. No statistical difference in mortality could be demonstrated for patients who had previous anginal symptoms vs those who did not, nor was age a predictor of mortality. Women had the same risk of death as men at 2 years after OHVF, but a significantly higher risk by year 6. Myocardial infarction associated with OHVF did not predict lower mortality throughout the study.

To ascertain if myocardial ischemia is the mechanism of out-of-hospital ventricular fibrillation (VF), left ventricular (LV) function was assessed at rest and during submaximal exercise in 15 patients who survived out-of-hospital VF. They were separated into asymptomatic (9 patients, group A) and symptomatic (6 patients, group S) groups for a history of angina or myocardial infarction. Both groups had significant (at least 70% diameter stenosis) coronary artery disease. At catheterization no patient had angina during exercise, but 12 of 15 had ST depression or increased ST depression (group A, 1.9 +/- 1.4 mm; group S, 1.1 +/- 1.2 mm) and 11 had abnormal wall motion. From rest to exercise, patients in group S had increased LV end-diastolic pressure (from 21 +/- 9 to 37 +/- 11 mm Hg, p = 0.009) and volume (from 100 +/- 25 to 107 +/- 26 ml/m2, p = 0.006), with no significant change in LV ejection fraction (from 40 +/- 13 to 42 +/- 12%). In group A LV end-diastolic pressure increased from 19 +/- 4 to 31 +/- 8 mm Hg (p = 0.001), but neither end-diastolic volume nor ejection fraction changed significantly (from 83 +/- 13 to 92 +/- 23 ml/m2 and from 55 +/- 13% to 46 +/- 13%, respectively). Thus, patients with coronary artery disease who survive out-of-hospital VF may have evidence of myocardial ischemia during exercise without pain. Painless ischemia may have a role in out-of-hospital VF.